Kampinga H H
Department of Cell Biology, Section of Radiation and Stress Cell Biology, Faculty of Medical Sciences, University of Groningen, The Netherlands.
Handb Exp Pharmacol. 2006(172):1-42. doi: 10.1007/3-540-29717-0_1.
A variety of cellular internal and external stress conditions can be classified as proteotoxic stresses. Proteotoxic stresses can be defined as stresses that increase the fraction of proteins that are in an unfolded state, thereby enhancing the probability of the formation of intracellular aggregates. These aggregates, if not disposed, can lead to cell death. In response to the appearance of damaged proteins, cells induce the expression of heat shock proteins. These can function as molecular chaperones to prevent protein aggregation and to keep proteins in a state competent for either refolding or degradation. Most knowledge of the function and regulation (by co-factors) of individual heat shock proteins comes from cell free studies on refolding of heat- or chemically denatured, purified proteins. Unlike the experimental situation in a test tube, cells contain multiple chaperones and co-factors often moving in and out different subcompartments that contain a variety of protein substrates at different folding states. Also, within cells folding competes with the degradative machinery. In this chapter, an overview will be provided on how the main cytosolic/nuclear chaperone Hsp70 is regulated, what is known about its interaction with other main cytosolic/nuclear chaperone families (Hsp27, Hsp90, and Hsp110), and how it may function as a molecular chaperone in living mammalian cells to protect against proteotoxic stresses.
多种细胞内外部应激条件可归类为蛋白毒性应激。蛋白毒性应激可定义为增加未折叠状态蛋白质比例、从而提高细胞内聚集体形成概率的应激。这些聚集体若不清除，可导致细胞死亡。为应对受损蛋白质的出现，细胞会诱导热休克蛋白的表达。这些热休克蛋白可作为分子伴侣发挥作用，防止蛋白质聚集，并使蛋白质保持能够重新折叠或降解的状态。关于单个热休克蛋白的功能及其（由辅助因子介导的）调控的大多数知识，来自对热变性或化学变性的纯化蛋白质进行复性的无细胞研究。与试管中的实验情况不同，细胞含有多种伴侣蛋白和辅助因子，它们经常在不同的亚细胞区室中进出，这些区室含有处于不同折叠状态的各种蛋白质底物。此外，在细胞内，折叠过程与降解机制相互竞争。在本章中，将概述主要的胞质/核伴侣蛋白Hsp70是如何被调控的，已知它与其他主要的胞质/核伴侣蛋白家族（Hsp27、Hsp90和Hsp110）的相互作用情况，以及它在活的哺乳动物细胞中作为分子伴侣如何发挥作用以抵御蛋白毒性应激。
